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Published online 11 July 2005. doi:10.1083/jcb.200505061
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 2, 305-316
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Article

 A novel role for Gab2 in bFGF-mediated cell survival during retinoic acid–induced neuronal differentiation

Yingwei Mao and Angel W.-M. Lee

Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, MI 48105

Correspondence to Angel W.-M. Lee: awmlee{at}umich.edu

Gab proteins amplify and integrate signals stimulated by many growth factors. In culture and animals, retinoic acid (RA) induces neuronal differentiation. We show that Gab2 expression is detected in neurons in three models of neuronal differentiation: embryonic carcinoma (EC) stem cells, embryonic stem cells, and primary neural stem cells (NSCs). RA treatment induces apoptosis, countered by basic FGF (bFGF). In EC cells, Gab2 silencing results in hypersensitivity to RA-induced apoptosis and abrogates the protection by bFGF. Gab2 suppression reduces bFGF-dependent activation of AKT but not ERK, and constitutively active AKT, but not constitutively active MEK1, reverses the hypersensitization. Thus, Gab2-mediated AKT activation is required for bFGF's protection. Moreover, Gab2 silencing impairs the differentiation of EC cells to neurons. Similarly, in NSCs, Gab2 suppression reduces bFGF-dependent proliferation as well as neuronal survival and production upon differentiation. Our findings provide the first evidence that Gab2 is an important player in neural differentiation, partly by acting downstream of bFGF to mediate survival through phosphoinositide 3 kinase–AKT.

Abbreviations used in this paper: AlexaFluor, AF; bFGF, basic FGF; EC, embryonic carcinoma; ES, embryonic stem; FGFR, FGF receptor; GFAP, glial fibrillary acidic protein; LY, LY294002; NSC, neural stem cell; PH, pleckstrin homology; PI3K, phosphoinositide 3 kinase; PIP3, phosphatidylinositol-3,4,5-P3; PY, phosphotyrosine; RA, retinoic acid; shRNA, small hairpin RNA; SVZ, subventricular zone; WT, wild type.


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